Utilizing a newly developed technique, the glucose clamp, in combination with the hepatic venous catheter and tritiated glucose tracer studies, we propose to investigate the relative contributions of tissue insensitivity to insulin and beta cell insensitivity to glucose in diabetics with varying degrees of carbohydrate intolerance. The site(s) of insulin resistance (decreased peripheral glucose utilization, decreased hepatic glucose uptake, augmented hepatic gluconeogenesis) will be defined and the contribution of each to the glucose intolerance will be quantitated. Changes in tissue sensitivity to insulin and beta cell secretion will be examined sequentially in untreated diabetics and in diabetics treated with oral hypoglycemic agents, insulin and/or diet. Special emphasis will be given to defining the interaction between hyperglycemia and hyperinsulinemia on the inhibition of hepatic glucose production and on hepatic glucose uptake in diabetic and normal subjects. The role of gastrointestinal factors in the stimulation of hepatic glucoseuptake and insulin secretion will be examined employing a combined intravenous-oral glucose clamp and contrasted in diabetics and normals. Studies will also be performed to determine whether the insulin resistance observed for carbohydrate metabolism also extends to amino acid and potassium metabolism. Lastly, the effects of epinephrine, propranolol, metabolic acidosis, and hyperketonemia on tissue sensitivity to insulin will be evaluated.